Clinical and preclinical activity of 2',2'-difluorodeoxycytidine (gemcitabine).
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Animals↗
Biomedical subjects
H H Hansen
Publications and source records attributed to H H Hansen.
Ceftriaxone versus latamoxef in febrile neutropenic patients: empirical monotherapy in patients with solid tumours.
121 patients with 132 febrile episodes were randomised to ceftriaxone or latamoxef monotherapy in order to compare antibiotic efficacy in neutropenic patients treated with cytotoxic chemotherapy for solid tumours. In 80 evaluable episodes no significant differences were observed between the two groups with respect to efficacy and fatal failure rates. Of episodes treated with ceftriaxone, 67% showed a favourable clinical response vs. 61% in the latamoxef group. The clinical response rates in episodes with documented bacterial infections were 67 and 56% in the two treatment groups. In 18% of the episodes with documented initial infections the patients died of presumably uncontrolled infection. The convenient once daily dosage schedule combined with fewer severe adverse reactions favours the use of ceftriaxone instead of latamoxef. Although a relative high degree of response was seen, empirical antibiotic monotherapy apparently does not offer a sufficient antibacterial cover in infections in this type of patient with defective host immunity.
Adult↗
Performance status assessment in cancer patients. An inter-observer variability study.
The ECOG Scale of Performance Status (PS) is widely used to quantify the functional status of cancer patients, and is an important factor determining prognosis in a number of malignant conditions. The PS describes the status of symptoms and functions with respect to ambulatory status and need for care. PS 0 means normal activity, PS 1 means some symptoms, but still near fully ambulatory, PS 2 means less than 50%, and PS 3 means more than 50% of daytime in bed, while PS 4 means completely bedridden. An inter-observer variability study of PS assessment has been carried out to evaluate the non-chance agreement among three oncologists rating 100 consecutive cancer patients. Total unanimity was observed in 40 cases, unanimity between two observers in 53 cases, and total disagreement in seven cases. Kappa statistics reveal the ability of the observers compared to change alone and were used to evaluate non-chance agreement. Overall Kappa was 0.44, (95% confidence limits 0.38-0.51). The Kappa for PS 0 was 0.55 (0.44-0.67), while those for PS 1, 2, 3 and four were 0.48 (0.37-0.60), 0.31 (0.19-0.42), 0.43 (0.32-0.55), and 0.33 (0.33-0.45), respectively. If one observer allocated patients to PS 0-2, then another randomly selected observed placed the patients in the same category with a probability of 0.92. For patients with PS 3-4 the probability that the same category would be chosen was 0.82. Overall, the non-chance agreement between observers was only moderate, when all ECOG Performance Status groups were considered. However, agreement with regard to allocation of patients to PS 0-2 versus 3-4 was high. This is of interest because this cut-off is often used in clinical studies.
Activities of Daily Living↗
Differential cytotoxicity of 19 anticancer agents in wild type and etoposide resistant small cell lung cancer cell lines.
A panel of six 'wild type' and three VP-16 resistant small cell lung cancer (SCLC) cell lines is used to evaluate to what extent in vitro sensitivity testing using a clonogenic assay can contribute to combine cytotoxic drugs to regimens with improved efficacy against SCLC. The resistant lines include (a) H69/DAU4, which is classical multidrug resistant (MDR) with a P-glycoprotein efflux pump (b) NYH/VM, which exhibits an altered topoisomerase II (topo II) activity and (c) H69/VP, which is cross-resistant to vincristine, exhibits a reduced drug accumulation as H69/DAU4 but is without P-glycoprotein. 19 anticancer agents were compared in the panel. The MDR lines demonstrated, as expected, cross-resistance to all topo II drugs, but also different patterns of collateral sensitivity to BCNU, cisplatin, ara-C, hydroxyurea, and to the topo I inhibitor camptothecin. The complete panel of nine cell lines clearly demonstrated diverse sensitivity patterns to drugs with different modes of action. Correlation analysis showed high correlation coefficients (CC) among drug analogues (e.g. VP-16/VM-26 0.99, vincristine/vindesine 0.89), and between drugs with similar mechanisms of action (e.g. BCNU/Cisplatin 0.89, VP-16/Doxorubicin 0.92), whereas different drug classes demonstrated low or even negative CC (e.g. BCNU/VP-16 -0.21). When the CC of the 19 drug patterns to VP-16 were plotted against the CC to BCNU, clustering was observed between drugs acting on microtubules, on topo II, alkylating agents, and antimetabolites. In this plot, camptothecin and ara-C patterns were promising by virtue of their lack of cross-resistance to alkylating agents and topo II drugs. Thus, the differential cytotoxicity patterns on this panel of cells can (1) give information about drug mechanism of action, (2) enable the selection and combination of non-cross-resistant drugs, and (3) show where new drugs 'fit in' among established agents.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
New cytostatic drugs in ovarian cancer.
BACKGROUND: Many ovarian cancer patients will after treatment of the recurrence with cisplatin based therapy enter phase I or II studies with new drugs. Lately, some new agents have shown activity. MATERIALS AND METHODS: The review is based on phase II studies mainly and focuses on paclitaxel (taxol). RESULTS: A Canadian/European study of high (175 mg/m2) versus low dose (135 mg/m2), and short (3 hours) versus long (24 hours) infusion confirms the reported activity of paclitaxel in previously treated patients. The preliminary overall response rate in 286 evaluable patients is 18.5%. A dose effect exists regarding neuropathy and neutropenia, and a longer infusion duration results in a higher frequency of grade 4 neutropenia. In a phase III study comparing cisplatin 75 mg/m2 plus cyclophosphamide (750 mg/m2) or plus paclitaxel 135 mg/m2 over 24 hours, the paclitaxel-based combination gave a superior response rate (54% versus 33%) and statistically significant longer progression-free interval. The semisynthetic docetaxel (taxotere) gives an overall response rate of 32% (95% confidence interval 23%-43%). Skin toxicity and edema are dose-limiting factors. Gemcitabine has also shown activity in platinum-resistant patients with an overall response rate of 23% (95% CI 10%-40%). CONCLUSIONS: The role of new drugs in first-line therapy remains to be seen. Further development of experimental work for screening and evaluation of new agents is needed.
Antimetabolites, Antineoplastic↗
Intratumoral pharmacokinetic analysis by 19F-magnetic resonance spectroscopy and cytostatic in vivo activity of gemcitabine (dFdC) in two small cell lung cancer xenografts.
BACKGROUND: Gemcitabine, 2'2'difluoro-deoxycytidine (dFdC), has shown activity in several preclinical models, and presently the compound is being clinically evaluated in patients with lung cancer and other solid tumors. DESIGN: The cytostatic in vivo activity of dFdC was tested in the two human small cell lung cancer (SCLC) tumor xenografts CPH SCCL 54A and 54B in nude mice. Non-invasive monitoring of the uptake and elimination of fluorine in the individual tumors was performed by in vivo 19F-magnetic resonance spectroscopy, using a 2.9 T magnet. Five dose levels in the range 5-80 mg/kg i.p. every third day, four times were applied. RESULTS AND CONCLUSION: Significant activity of gemcitabine was demonstrated in both SCLC tumor lines. The tumor line 54A is the most sensitive to radiotherapy, doxorubicin, and nitrosoureas; but in this case the 54B tumors were more sensitive to gemcitabine therapy than 54A. This difference in sensitivity seems to be related to different delivery or uptake of the compound in the two tumor lines, since the 19F-MRS demonstrated a significantly higher antitumor accumulation of fluorine in 54B tumors compared with 54A (p < 0.05, Wilcoxons 2-sided test) following the same single dose of the drug.
Animals↗
A phase II study of ifosfamide, carboplatin and cisplatin in advanced and recurrent squamous cell carcinoma of the uterine cervix.
BACKGROUND: Discouraging response duration and long-time survivals have so far been the result of cisplatin-containing combination chemotherapy against advanced or recurrent squamous cell carcinoma of the uterine cervix. In order to increase the platinum-based effect upon this tumor without an increase in the specific toxicity of cisplatin, we combined it with carboplatin, added ifosfamide, which has been shown to possess a comparable degree of single-agent activity. PATIENTS AND METHODS: Thirty-six patients with advanced or recurrent squamous cell carcinoma of the uterine cervix not curable by radiation or surgery were treated with a combination of ifosfamide 1.5 gr/m2 i.v. days 1-3, carboplatin 200 mg/m2 i.v. day 1, and cisplatin 50 mg/m2. Thirty-one patients were evaluable for response and 34 patients for toxicity. RESULTS: Twenty-three patients responded (64%), 11 (31%) of them completely, and 12 (33%) partially. Median response duration was 23 weeks (range 8-107 weeks), reaching 27 weeks and 21 weeks for patients with and without disease in previously irradiated areas, respectively. Median survival is 40 weeks (range 1-114 weeks). Toxicity consisted mainly of moderate to severe myelosuppression, resulting in 2 toxic deaths. CONCLUSION: The response rate, also for earlier irradiated areas, compares favorably with other known cisplatin-containing regimens. The combination deserves investigation in a randomized setting.
Adult↗
Prospective evaluation of the effect on initial brain metastases from small cell lung cancer of platinum-etoposide based induction chemotherapy followed by an alternating multidrug regimen.
BACKGROUND: During the 1980s reports describing the effect of systemic chemotherapy on brain metastases from chemosensitive tumours emerged, including a few retrospective reports on small cell lung cancer (SCLC) patients. DESIGN: Previously untreated SCLC patients with no other malignancy, but in some cases with mixed histological subtype, who had symptomatic brain metastases verified by contrast enhanced CT-scan, were treated with a multidrug combination chemotherapy regimen and no cranial irradiation. Radiotherapy was optional at cranial relapse or progression at the discretion of the physician in charge. The intracranial effect was evaluated by 4-weekly CT-scan and neurological examination, according to a standardized scoring system. END POINTS: Intracranial response, duration of response, neurological score, terminal CNS status, and survival. RESULTS: 21 patients were included, corresponding to 8.6% of consecutive SCLC patients at our institution. 8 patients died before follow-up leaving 13 evaluable for response. In the former group, all patients had WHO performance status of 3-4 compared to 6/13 in the latter group. Of the 13 evaluable patients, 1 had early progression in the CNS and 1 had no change. 11 had CT-scan verified response, with a median duration of 135 days. Most patients, including all complete responders, had improvement in their neurological score. 6 out of 11 responders died without active CNS disease. The crude median survival was 111 days, whereas the median survival (early deaths excluded) was 197 days. CONCLUSION: Systemic combination chemotherapy was effective for palliation of initial brain involvement in the majority of patients in a small consecutive series. The role of consolidating cranial irradiation in responders should be assessed by a randomized trial.
Aged↗
Lung cancer.
In small cell lung cancer, combination chemotherapy including agents such etoposide, teniposide, cisplatin, doxorubicin, ifosfamide, vincristine and cyclophosphamide continues to be the cornerstone of therapy. The importance of dose scheduling of etoposide with continuous treatment of 5 days' duration or more is becoming more and more clear. Complete or partial responses secondary to combination chemotherapy occur in 80-90% of all patients with median durations of 9 to 11 months. Median survival in these studies is unchanged, at present 11-16 months depending on the initial tumour stage. The optimum duration of treatment is still uncertain, but generally a period of 6 to 9 months is used. The use of G-CSF with combination chemotherapy leads to reductions in the incidence of fever, duration and severity of grade 4 neutropenia, and in the total number of days of treatment with i.v. antibiotics and days of hospitalization. No differences have been observed in response rates, duration of response or survival. Therapeutic results for epidermoid, cancer, adeno carcinoma, large cell carcinoma and mesothelioma are essentially unchanged. The treatment of patients with these tumours should continue to be considered experimental since no standard chemotherapy has as yet been developed, neither when given as single modality nor in combination with surgery or radiotherapy. Two studies published in 1991 comparing induction chemotherapy before irradiation versus irradiation alone have resulted in improvement of median and 2-year survival, while a third study did not show such an improvement. The fact remains that three-fourths of patients with local disease die within 3 years, and further improvements in both systemic and local treatment are needed.
Adenocarcinoma↗
[Clinical picture of acute pulmonary embolism. Relations to the degree of vascular obstruction].
In 132 consecutive patients treated for pulmonary embolism, duration of symptoms, number of embolic episodes before the diagnosis, circulatory affection (stable circulation (n = 61), reversible shock (n = 60), circulatory collapse (n = 11), electrocardiographic findings and systolic pulmonary pressure (n = 60) were analysed in relation to 1) underlying diseases (orthopedic surgical patients (n = 43), gynecological-abdominal surgical patients (n = 22), preembolic healthy patients (n = 42), miscellaneous medical patients (n = 25)), and 2) the obstruction of the pulmonary vascular bed quantified by a scintigraphic or angiographic score. While embolic score did not differ between the groups of underlying diseases, preembolic healthy patients with deep vein trombosis (n = 30) had longer mean duration of symptoms (14 days), more embolic episodes, (1.7 episode) and higher pulmonary pressure (72 mmHg) than the material on an average with values of 7 days, 0.9 episodes and 57 mmHg, respectively (p less than 0.001). Among patients with reversible shock or circulatory collapse, half had at least one previous embolic episode, one fifth from two to four. Embolic score correlated well with the circulatory affection (p less than 0.001). A high pulmonary pressure correlated with long duration of symptoms and a high number of embolic episodes (p less than 0.002). Sinus tachycardia and electrocardiographic signs of acute right ventricular strain (complete and incomplete right bundle branch block, SIQIIITIII-pattern and inverted T-waves in V2-4) correlated positively to the circulatory affection and inversely to duration of symptoms and number of embolic episodes (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
[Aggressive treatment of acute pulmonary embolism. 132 consecutive patients treated with heparin, streptokinase or embolectomy, 1975-1987].
During 1975-1987, 132 patients were treated for acute pulmonary embolism with heparin (n = 41), streptokinase (n = 52), or embolectomy (n = 39). In 1984, the indications for embolectomy were broadened to include all patients with central emboli, also those who were circulatory stable. The heparin-, streptokinase-, and embolectomy groups differed from each other as regards the degree of circulatory impairment (stable circulation/reversible shock/circulatory collapse: 68/32/0% versus 52/48/0% versus 16/56/28%, p less than 0.0001) and embolic score (20 for complete obstruction; 5.6 +/- 3.4 versus 8.7 +/- 2.8 versus 13.2 +/- 2.4, p less than 0.0001), but were comparable in terms of prognosis (30-day mortality/10-year survival +/- standard error: 7%/61 +/- 9% versus 13%/59 +/- 9% versus 18%/61 +/- 10%). Stable circulation, reversible shock, and circulatory collapse prior to embolectomy resulted in 30-day mortalities of 0%, 9%, and 45% respectively (p less than 0.01). During 1984-1987, no early or late deaths after embolectomy were observed in patients without circulatory collapse (n = 10). In comparable patients (embolic score greater than or equal to 9, symptom duration less than or equal to 7 days, no circulatory collapse), streptokinase treatment (n = 13) and embolectomy (n = 25) resulted in 10-year survival +/- standard error of 46 +/- 16% and 82 +/- 10% respectively (p less than 0.0001) and in an embolic score-reduction (score before minus score after treatment) of 5.7 +/- 2.3 and 10.5 +/- 2.9, respectively (p less than 0.0001). Embolectomy during extracorporeal circulation should be considered the treatment-of-choice in patients with acute central emboli.
Acute Disease↗
Management of small-cell cancer of the lung.
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Carcinoma, Small Cell↗
Doxorubicin sensitivity pattern in a panel of small-cell lung-cancer cell lines: correlation to etoposide and vincristine sensitivity and inverse correlation to carmustine sensitivity.
The aim of our investigations is to evaluate whether the sensitivity patterns of small-cell lung-cancer (SCLC) cell lines in vitro can be used in evaluating new drugs and in selecting drugs for the optimization of combination therapy. In our attempts to obtain a panel of cell lines demonstrating differential patterns in sensitivity, we have developed three SCLC lines exhibiting different types of multidrug resistance (MDR). In the present investigations we compared the sensitivity patterns shown by five wild-type SCLC lines and three MDR lines in response to six different types of drugs: doxorubicin, cytarabine, carmustine, cisplatin, vincristine, and etoposide. In the wild-type SCLC cell lines, the range of variation in sensitivity to all drugs was within a factor of 10. Cell lines showing low sensitivity to doxorubicin also exhibited low sensitivity to etoposide and vincristine, and vice versa. In contrast, the pattern of sensitivity to carmustine was almost the opposite of that to doxorubicin. A tendency to an inverse relationship between doxorubicin and carmustine sensitivity was also observed when doxorubicin sensitivity was reduced in near stationary cells and in cells exposed to the metabolic inhibitor 2-deoxy-D-glucose. In agreement with the pattern observed for the wild-type lines, all of the MDR sublines demonstrated collateral sensitivity to carmustine. As to cytarabine, the wild-type lines expressed a sensitivity pattern similar to that shown in response to doxorubicin. Interestingly, the opposite pattern was found in the MDR lines, as all three demonstrated cytarabine hypersensitivity. The combination of alkylating agents and "MDR" drugs are of proven clinical benefit in the treatment of solid tumors, as is the combination of anthracycline and cytarabine in acute myeloid leukemia. The experimentally derived sensitivity data on cytarabine, alkylating agents, and MDR drugs (i.e., etoposide, doxorubicin, vincristine) thus resemble the clinical experience with these drugs, and we conclude that the use of a clonogenic assay on the described panel of SCLC cell lines can give valuable information for the selection of agents for combination therapy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Serum neuron specific enolase (NSE) is a determinant of response duration in small cell lung cancer (SCLC).
Seventy-two consecutive patients were eligible for a study of clinical determinants of response and response duration in small cell lung cancer (SCLC). Pretreatment values of routine laboratory parameters, and three tumour markers: neuron specific enolase (NSE), carcinoembryonic antigen (CEA), and acidic glycoprotein (AGP) were measured. Descriptive clinical variables as performance status (PS), extent of disease, age and sex were also included in the study. All variables were analysed for influence on the type and duration of response. The complete remission probability was only related to pretreatment extent of disease. In a multivariate analysis (Cox) of response duration, only NSE and type of response had significant influence. Consequently, measurements of NSE before therapy will be useful in future clinical trials on SCLC especially in situations, where responding patients are submitted to specific treatment strategies.
Adult↗
Ways to a better treatment of small cell lung cancer--a commentary.
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Carcinoma, Small Cell↗
The impact of abdominal computerized tomography on the pretreatment staging and prognosis of small cell lung cancer.
One hundred six patients with small cell lung cancer (SCLC) were prospectively evaluated with regard to the prognostic impact of abdominal CT-scan in the pretreatment staging when compared to ultrasonography of the abdomen. Staging based on abdominal ultrasonography (US) plus bilateral bone marrow examinations gave as a result that 47 patients had extensive disease (ED) (44%). Seventeen patients with proven ED at time of referral were not included in this study. Abdominal CT-scan was performed in 76 of the 106 patients. Thirty patients of these 76 patients (39%) were classified as having ED after staging including US, but abdominal metastases were disclosed in another ten patients at the subsequent CT-scan. Liver metastases seen in two patients at ultrasonography were overlooked on the CT-scans. Median survival of the 36 patients classified as having limited disease (LD) after both procedures was 458 days, which was significantly better compared to 330 days for the ten patients with stage migration from LD to ED based on CT-scan, (p less than 0.05) and compared to 242 days in the 30 patients with ED demonstrated by both US and CT-scans (p less than 0.05). The prognostic impact of the CT-scan was further investigated in a multivariate analysis (Cox). Stage disease, performance status, LDH and alkaline phosphatase were significant prognostic factors in a proportional hazards model based on the original 106 patients. Patients in the best prognostic group were characterized by LD, good performance status (0-1) and normal LDH and alkaline phosphatase serum values. This group consisted of 22 patients (21%).(ABSTRACT TRUNCATED AT 250 WORDS)
Abdominal Neoplasms↗
Metastatic spinal cord compression secondary to lung cancer.
PURPOSE: Metastatic spinal cord compression (MSCC) is a disabling complication to cancer, the optimal treatment for which is not settled. An analysis was performed for all patients with MSCC secondary to lung cancer in East Denmark from 1979 to 1988. PATIENTS AND METHODS: The total series included 102 cases with small-cell carcinoma (SCLC; 40%), adenocarcinoma (ACL; 26%), squamous cell carcinoma (SQLC; 18%) and large-cell carcinoma (LCC; 9%). Symptoms, clinical presentations, and therapeutic results are described. RESULTS: The outcome of treatment depended fundamentally on the patient's neurologic condition at the time of the diagnosis. All patients with SCLC who were able to walk at the time of MSCC remained ambulatory, whereas 15% of the nonambulatory SCLC patients regained walking ability. In non-SCLC, 95% of patients continued to be able to walk, whereas 22% regained the ability to walk. No major differences in the immediate outcome of treatment between the various histologic types of lung cancer and the different treatment modalities were observed; however, 82% of the patients with non-SCLC benefited from treatment with laminectomy followed by radiotherapy (RT) compared with either laminectomy (47%) or RT (39%) alone (P = .03, chi 2 test). The group of patients who were treated with laminectomy followed by RT had a better survival (median value, 3.5; range, 0 to 132 months) than patients who were treated with either laminectomy (median value, 1.5; range, 0 to 32 months) or RT (median value, 1; range, 0 to 59 months) alone (P = .03, log-rank test). No significant difference was observed in survival between the various histologic types of lung cancer (P = .18, log-rank test). CONCLUSION: Despite a short survival, early diagnosis and immediate treatment is crucial because it may preserve the gait function in 97% of lung cancer patients who develop malignant spinal cord compression.
Adenocarcinoma↗
Systemic chemotherapy of brain metastases from small-cell lung cancer: a review.
PURPOSE: For decades the treatment of choice in small-cell lung cancer (SCLC) with brain metastases has been corticosteroids and radiotherapy (RT) because of a presumed lack of penetrance of cytostatic agents into parenchymatous brain metastases. In recent years, several reports have appeared on radiologic and clinical responses to systemic chemotherapy without additional RT in patients with metastatic SCLC in the brain. We reviewed the literature and focused on the methodologic aspects in comparison with RT data. DESIGN: We reviewed 12 patient series that included 116 patients and were published between 1981 and 1990. RESULTS: The overall brain response to chemotherapy without irradiation in patients with intracranial metastases at diagnosis was 76%, whereas the response rate of brain relapses was 43%. CONCLUSIONS: We conclude that intracranial metastases from SCLC seem to respond to chemotherapy as readily as other metastatic locations of SCLC do. Thus first-line cranial irradiation probably should be applied routinely only in cases of delayed brain metastases. Whether consolidating cranial RT should be given after a few courses of initial chemotherapy in SCLC patients with brain metastases at diagnosis is unclear and warrants a randomized evaluation.
Antineoplastic Combined Chemotherapy Protocols↗