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Biomedical subjects

N van Zandwijk

Publications and source records attributed to N van Zandwijk.

At least 19 recordsLinked to original sources
PubMed1999

Chemoprevention of head and neck and lung (pre)cancer.

Oral cancer is often preceded by precancerous lesions, the most common of which is leukoplakia. Several treatment modalities are available: elimination of the possible cause, cold knife, laser, or cryosurgery, and topical application of bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to study the value of chemoprevention as a strategy to prevent cancer, because its effect is directly visible and material for analysis is easily obtainable from the mouth. In several studies and chemoprevention trials the efficacy of retinoids, retinol and/or beta-carotene on oral leukoplakia has been demonstrated. Second primary tumors occur in 10-30% of head and neck cancer patients and 10% of lung cancer patients. Chemoprevention offers an attractive approach to combat this threat to such patients, which is bound to cast a shadow over their lives. In the last 10-15 years several chemoprevention studies with vitamin A, retinoids or agents working through other mechanisms (antioxidants) have been launched. The largest chemoprevention study in curatively treated early-stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an EORTC study initiated in 1988. End-points are second tumors, local/regional recurrence and distant metastases, and long-term survival rates. Preminary results will be available in 1998.

Biomarkers, Tumor↗
PubMed1999

Teniposide sometimes effective in brain metastases from non-small cell lung cancer.

In a prospective study we have treated 13 patients with brain metastases from non-small cell lung cancer with intravenous teniposide, at a dose of 150 mg/m2 on days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13 patients had previously been treated for brain metastases by surgery and/or radiotherapy. Seven patients experienced neurological improvement. Objective response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5 patients. Duration of response in the 3 patients with objective response was 16 weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial disease responded also to teniposide therapy. Although toxicity of teniposide therapy was relatively mild, there was one patient who died as a consequence of leukopenic sepsis. The results demonstrate that teniposide has some activity in de novo as well as recurrent brain metastases from non-small cell lung cancer.

Aged↗
PubMed1998

Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: To compare two cisplatin based chemotherapy schedules in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 332 patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day 1 either in combination with teniposide 100 mg/m2 on days 1, 3, and 5 (arm A) or paclitaxel 175 mg/m2 by 3-hour infusion on day 1 (arm B); cycles were repeated every 3 weeks. RESULTS: Fifteen patients were ineligible; patient characteristics were well balanced between the two arms: 71% were male, 71% had less than 5% weight loss, 89% had a World Health Organization (WHO) performance status of 0 to 1, 51% had adenocarcinoma, and 61% had stage IV disease. Hematologic toxicity was significantly more severe in arm A (leukopenia, neutropenia, and thrombocytopenia grade 3 or 4: 66% v 19%, 83% v 55%, 36% v 2% in arms A and B, respectively), which resulted in more febrile neutropenia (27% v 3% in arms A and B, respectively), dose reductions, and treatment delays. There were a total of nine toxic deaths, six due to neutropenic sepsis: five in arm A and one in arm B. In contrast, arthralgia/myalgia (grade 2 or 3, 4% v 17%), peripheral neurotoxicity (grade 2 or 3, 6% v 29%), and hypersensitivity reactions (1% v 7%, all grades) were significantly more frequent in arm B. The frequency and severity of other toxicities were comparable between the two arms. Responses were one complete and 44 partial on arm A (28%) and two complete and 61 partial (41%) on arm B (P = .018). There was no significant difference in survival, with median and 1-year survivals 9.9 versus 9.7 months and 41% versus 43%, respectively in arm A and B. Progression-free survival was 4.9 and 5.4 months in arm A and B, respectively. Selected centers participated in a quality-of-life (QoL) assessment, which was performed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and LC-13 administered at baseline and every 6 weeks thereafter. Arm B achieved a better score at week 6 for emotional, cognitive and social functioning, global health status, fatigue, and appetite loss, which was lost at 12 weeks. In conclusion, arm B appears superior to arm A with regard to response rate, side effects, and QoL. CONCLUSION: Although survival was not improved, arm B offers a better palliation for advanced NSCLC patients than arm A.

Adult↗
PubMed1998

The use of 4-aminobiphenyl hemoglobin adducts and aromatic DNA adducts in lymphocytes of smokers as biomarkers of exposure.

Two biomarkers of exposure to cigarette smoke, 4-aminobiphenyl-hemoglobin (Hb) adducts and aromatic DNA adducts in lymphocytes, were determined from a population of 55 smokers and 4 nonsmokers. The levels of these adducts were related to daily cigarette consumption and also to (calculated) tar and nicotine intake. The Hb adduct levels seemed to correspond best to the number of cigarettes (cig) smoked, but at a cigarette consumption of >30 cig/day, a saturation effect was observed. Lymphocytic DNA adducts also correlated well with cigarette and tar consumption; for this type of adduct, a saturation level was reached at a dose of approximately 15-20 cig/day. From a subpopulation, a second sample was obtained after 2 months, and the adduct levels were compared with their initial adduct levels. Strong correlations were found between the first and second DNA adduct measurements (r = 0.84). In another subpopulation, resampling was performed after 6 months. No correlation between DNA adduct levels in the first and last samples was found, but 4-aminobiphenyl Hb adduct levels were strongly correlated (r = 0.78), the absolute quantities measured being comparable (paired t test: t = -1.27, P = 0.22, n = 15). We found no influence of GSTM1 and NAT2 polymorphisms on Hb adduct formation and of GSTM1 polymorphism on aromatic DNA adduct formation. A significantly lower aromatic DNA adduct level was observed for intermediate acetylators when compared to slow acetylators.

Adult↗
PubMed1997

Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group.

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.

Antineoplastic Agents↗
PubMed1997

Etoposide in malignant pleural mesothelioma: two phase II trials of the EORTC Lung Cancer Cooperative Group.

Intravenous and oral etoposide (VP 16-213) were tested in two sequential phase II trials in chemotherapy-naive patients with malignant pleural mesothelioma. In the first trial, etoposide was given intravenously (i.v.) at a dose of 150 mg/m2 on days 1, 3 and 5 every 3 weeks. The second trial investigated a daily oral dose of 100 mg for 21 days followed by a 2-week treatment-free period, and then recycling. In both trials, the treatment was given until disease progression, intolerable toxicity or patient refusal. In the i.v. trial, 49 patients were included, 2 patients were ineligible. The oral trial recruited 45 patients, 4 patients were not eligible. In both trials, the main side-effects were moderate leucopenia, alopecia, nausea and vomiting. Two partial responses (4%) and three partial responses (7%) were reported in the i.v. and oral trials, respectively. The median survival was 29 weeks and 38 weeks in the i.v. and oral trials, respectively. In conclusion, further investigation of etoposide in malignant mesothelioma is not recommended.

Administration, Oral↗
PubMed1997

Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies.

Five patients with a pleural malignancy (four malignant mesotheliomas and one localized low grade carcinoid) were treated with maximal surgical resection of the tumour followed by intraoperative adjuvant photodynamic therapy (PDT). The additional photodynamic treatment was performed with light of 652 nm from a high power diode laser, and meta-tetrahydroxy phenylchlorin as the photosensitizer. The light delivery to the thoracic cavity was monitored by in situ isotropic light detectors. The position of the light delivery fibre was adjusted to achieve optimal light distribution, taking account of reflected and scattered light in this hollow cavity. There was no 30-day post-operative mortality and only one patient suffered from a major complication (diaphragmatic rupture and haematopericardium). The operation time was increased by a maximum of 1 h to illuminate the total hemithoracic surface with 10 J cm(-2) (incident and scattered light). The effect of the adjuvant PDT was monitored by examination of biopsies taken 24 h after surgery under thoracoscopic guidance. Significant damage, including necrosis, was observed in the marker lesions with remaining malignancy compared with normal tissue samples, which showed only an infiltration with PMN cells and oedema of the striated muscles cells. Of the five patients treated, four are alive with no signs of recurrent tumour with a follow-up of 9-11 months. One patient was diagnosed as having a tumour dissemination in the skin around the thoracoscopy scar and died of abdominal tumour spread. Light delivery to large surfaces for adjuvant PDT is feasible in a relatively short period of time (< 1 h). In situ dosimetry ensures optimal light distribution and allows total doses (incident plus scattered light) to be monitored at different positions within the cavity. This combination of light delivery and dosimetry is well suited for adjuvant treatment with PDT in malignant pleural tumours.

Adult↗
PubMed1997

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.

Adenocarcinoma↗
PubMed1997

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

Adult↗
PubMed1997

Clinical pharmacology of carboplatin administered in combination with paclitaxel.

The clinical pharmacology of carboplatin (C) administered with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (P) was investigated in two phase I studies undertaken in 83 previously untreated patients with either non-small cell lung cancer or ovarian cancer. Carboplatin was administered over 30 minutes and paclitaxel over 3 hours. Both agents were given every 4 weeks. Non-small cell lung cancer patients were randomized to two administration sequences, either carboplatin followed by paclitaxel (C-->P) or the reverse (P-->C). Each patient received the alternate sequence during the second and subsequent courses. Ovarian cancer patients uniformly received paclitaxel before carboplatin. Platinum concentrations in plasma ultrafiltrate were measured via flameless atomic absorption spectrometry, and 122 concentration-time curves were obtained. For non-small cell lung cancer patients, the mean area under the concentration-time curve (AUC) per 300 mg/m2 carboplatin was 3.52 mg/mL x min (range, 1.94 to 5.83) for the sequence C-->P and 3.62 mg/mL x min (range, 1.91 to 5.01) for the sequence P-->C. No sequence-dependent effect was observed (P > .5). For ovarian cancer patients, the mean AUC per 300 mg/m2 carboplatin was 3.83 mg/mL x min (range, 2.72 to 6.10), showing no difference when compared with data derived from non-small cell lung cancer patients (P = .13). In addition, the carboplatin AUC was not influenced by increasing paclitaxel doses from 100 to 250 mg/m2. Neutropenia was the principal toxicity, and anemia was frequent. However, there was a striking lack of thrombocytopenia. Modeling of the relationship between the carboplatin AUC and the decrease in platelets revealed a 50% decrease in platelets at a carboplatin AUC (AUC50) of 6.3 mg/mL x min. This contrasts with historical data documenting a carboplatin AUC50 of 4.0 mg/mL x min. Our findings suggest that there is a considerable interaction of both drugs at the cellular level, with at least an additive effect of carboplatin on the main hematologic toxicity of paclitaxel (ie, neutropenia). There is also a protective effect exerted by paclitaxel on carboplatin-related toxicity (ie, thrombocytopenia). The clear protective effect of paclitaxel in this combination suggests that it is possible to reduce the dose interval to 3 weeks. Studies are in progress to test this hypothesis and to investigate the underlying pharmacologic interactions.

Adult↗
PubMed1996

The toxicity of radiotherapy following high-dose chemotherapy with peripheral blood stem cell support in high-risk breast cancer: a preliminary analysis.

High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be hampered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.

Adenocarcinoma↗
PubMed1996

Photodynamic therapy: a promising new modality for the treatment of cancer.

The first reports on photodynamic therapy (PDT) date back to the 1970s. Since then, several thousands of patients, both with early stage and advanced stage solid tumours, have been treated with PDT and many claims have been made regarding its efficacy. Nevertheless, the therapy has not yet found general acceptance by oncologists. Therefore it seems legitimate to ask whether PDT can still be described as "a promising new therapy in the treatment of cancer". Clinically, PDT has been mainly used for bladder cancer, lung cancer and in malignant diseases of the skin and upper aerodigestive tract. The sensitizer used in the photodynamic treatment of most patients is Photofrin, (Photofrin, the commercial name of dihematoporphyrin ether/ester, containing > 80% of the active porphyrin dimers/oligomers (A.M.R. Fisher, A.L. Murphee and C.J. Gomer, Clinical and preclinical photodynamictherapy, Review Series Article, Lasers Surg. Med., 17 (1995) 2-31). It is a complex mixture of porphyrins derived from hematoporphyrin. Although this sensitizer is effective, it is not the most suitable photosensitizer for PDT. Prolonged skin photosensitivity and the relatively low absorbance at 630 nm, a wavelength where tissue penetration of light is not optimal, have been frequently cited as negative aspects hindering general acceptance. A multitude of new sensitizers is currently under evaluation. Most of these "second generation photosensitizers" are chemically pure, absorb light at around 650 nm or greater and induce no or less general skin photosensitivity. Another novel approach is the photosensitization of neoplasms by the induction of endogenous photosensitizers through the application of 5-aminolevulinic acid (ALA). This article addresses the use of PDT in the disciplines mentioned above and attempts to indicate developments of PDT which could be necessary for this therapy to gain a wider acceptance in the various fields.

Digestive System Neoplasms↗
PubMed1996

Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study.

Photodynamic therapy (PDT) using Photofrin was used in combination with a hypoxic toxin (mitomycin C, MMC) to treat four patients with recurrent skin metastasis of a mammary carcinoma. In preclinical experiments an additive effect was found for the combination of MMC and PDT for treating subcutaneous RIF1 tumours in mice. When interstitial PDT was combined with a low dose of MMC (administered 15 min before illumination), the Photofrin dose or light dose could be reduced by a factor of 2 in order to obtain equivalent cure rate or growth delay. In the clinical pilot study, a low dose of Photofrin (0.75 mg kg-1) was used for PDT alone (superficial illumination) or combined with low-dose MMC (5 mg m-2). Different tumour areas were illuminated with or without a preceding infusion of MMC. Both tumour response and skin photosensitivity were scored. After 8-12 weeks of treatment, tumour cure could be achieved by administering light doses > or = 150 J cm-2 for PDT alone and similar effects were obtained when light doses of 75-87.5 J cm-2 were given after infusion with MMC. In all cases necrotic tissue of both tumour and surrounding skin was observed, which lasted for a mean of 5 months (range 2-20 months). Skin phototoxicity, tested by using a standardised illumination of skin patches on the back, lasted maximally 3 weeks. Three main conclusions could be drawn from these studies: (1) The enhanced effects of the combination of PDT and MMC observed in mouse tumours can be extrapolated to patients with mammary skin metastasis. (2) The combination of PDT and hypoxic toxins facilitates treatment by permitting lower doses of photosensitiser to be used (thereby reducing skin phototoxicity) or lower light doses (thereby reducing illumination times and allowing the possibility to treat larger tumour areas). (3) Restoration of skin after PDT in previously treated tumour areas (chemotherapy, radiation therapy and surgery) is very low.

Aged↗
PubMed1996

Paclitaxel for malignant pleural mesothelioma: a phase II study of the EORTC Lung Cancer Cooperative Group.

The EORTC Lung Cancer Cooperative Group undertook a phase II study of paclitaxel in 25 chemotherapy-naive patients with malignant pleural mesothelioma. Paclitaxel was given intravenously at a dose of 200 mg m-2 as a 3 h infusion every 3 weeks, after standard premedication with corticosteroids and antihistamines. This regimen was well tolerated, with < 4% of cycles resulting in severe toxicity. No major objective responses were observed and ten patients had stable disease. Median survival time was 39 weeks and the 1 year survival rate was 30%. In conclusion, paclitaxel at the dose and schedule investigated in this trial had no major activity in the treatment of malignant pleural mesothelioma.

Adult↗
PubMed1996

Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: improvement of tumour uptake by internalisation.

The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLS) xenografts was studied in a Balb/c nu/nu mouse model. These Mabs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 125I, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after the administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. Mab 123C3 is internalised into tumour cells, whereas both other anti-NCAM Mabs are not. Internalisation into NCI H69 cells was demonstrated in vitro by radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabeled Mabs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results immunoscintigraphy.

Animals↗
PubMed1996

Oral ifosfamide/mesna versus intravenous ifosfamide/mesna in non-small-cell lung cancer: a randomized phase II trial of the EORTC lung cancer cooperative group.

BACKGROUND: Chronic oral administration of anticancer drugs may offer therapeutic advantages. PATIENTS AND METHODS: A total of 68 patients with advanced non-small-cell lung cancer, not previously treated by chemotherapy, were randomized to receive either ifosfamide given orally (OSI) at a dose of 1 g/day for 14 days every 4 weeks, or as a 1-hour intravenous infusion (IVI) at a dose of 1.6 g/m2/day for 5 days every 4 weeks. According to the route of ifosfamide administration, patients received either mesna i.v. or mesna film-coated tablets for uroprotection. RESULTS: Eight patients were found to be ineligible for the study and therefore excluded for all analyses. Thirty-three patients received IVI, and 27 patients OSI. One patient randomized to OSI died before treatment was initiated, leaving 59 patients fully evaluable for toxicity. Hematological toxicity was less severe for patients on OSI, but CNS toxicity was reported more frequently on OSI (39%; 12% grade III/IV), than on IVI (15%; 9% grade III/IV), which caused the premature close of the study. Other non-hematological adverse events were of modest clinical significance and comparable in both arms. Forty-nine patients were considered evaluable for response: in the IVI arm, 5 (17%) of the 29 evaluable patients obtained a partial remission, and 7 patients a no change (24%). In the OSI arm, 2 (10%) of the 20 evaluable patients obtained a partial remission, and 11 (52%) a stable disease. CONCLUSIONS: Both arms have some activity in non-small-cell lung cancer; while OSI was less myelosuppressive than IVI, it was associated with a higher incidence of CNS toxicity. Oral administration of ifosfamide, in the schedule and daily dose tested here cannot be recommended.

Administration, Oral↗
PubMed1996

Treatment of metastatic non-small cell lung cancer.

Although the overall survival rates for patients with metastatic non-small cell lung cancer have not changed in the past two decades, meta-analytic studies have confirmed that a modest increase in mean survival time can be gained with platinum-based combination chemotherapy. With appropriate selection of patients, chemotherapy will have symptomatic benefits in more than 60% of patients, and concerns regarding the costs of chemotherapy will be lessened by the observation that in some instances chemotherapy is less costly than best supportive care. Until the end of the 1980s, apart from the few active agents and their analogues no new drugs became available, but in the past 5 years several new agents have shown promising results and are now being included in combination programs. Large-scale comparative studies, looking for the combination with the best therapeutic index, are awaited with great interest. The number of patients with non-small cell lung cancer is so great that even modest improvements in therapy will have a great impact on survival rates.

Antineoplastic Agents↗