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Biomedical subjects

A Sandler

Publications and source records attributed to A Sandler.

At least 37 records · Page 2Linked to original sources
PubMed1999

Overexpression of Fas ligand does not confer immune privilege to a pancreatic beta tumor cell line (betaTC-3).

BACKGROUND: Fas ligand (Fas-L) is thought to provide immune privilege to specific tissues and tumors by inducing an apoptotic signal of cytotoxic T cells expressing its Fas receptor. Purpose. The purpose of this work was to evaluate whether an immortalized insulin-secreting cell line (betaTC-3) gains immune privilege by inducing overexpression of Fas-L. METHODS: A lipofection technique was used to transfect a betaTC-3 tumor cell line with a plasmid (pcDNA3.1/Zeo) carrying the Fas-L gene and a zeocin resistance gene. Insertion of Fas-L into betaTC was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants (betaTC-3/Fas-L) to induce apoptosis of Fas-sensitive T cells. Transfectants and control cells were tested for insulin secretion following which 1 x 10(6) insulin-secreting betaTC-3 and betaTC-3/Fas-L cells were subcutaneously implanted into syngeneic, allogeneic, and Fas mutant (lpr) syngeneic mice. Survival of the insulin-secreting cells was then determined by monitoring serum glucose levels in recipients. RESULTS: Successful transfection of vector resistance gene was achieved in the transfected betaTC-3 cells, which was confirmed by zeocin resistance. RT-PCR in resistant Fas-L clones confirmed the transcription of Fas-L, which was absent in controls. Fas-L transfectants induced 20 +/- 4.2% apoptosis of Fas-sensitive T cells, while controls induced 3.47 +/- 2.3% by flow cytometry (P = 0.04, n = 3). Insulin secretion was equivalent in both betaTC-3 and betaTC-3/Fas-L cells. Syngeneic mice implanted with control betaTC-3 cells died within 3 weeks from hypoglycemia due to overgrowth of betaTC-3 tumor. Implanted Fas-L transfected betaTC-3 cells were killed and had no effect on glycemic status except in Fas mutant hosts, where tumors formed in two of three mice. CONCLUSIONS: Despite the ability of transfected betaTC-3 cells to induce apoptosis of T cells in vitro, expression of Fas-L provided no immune privilege to these cells in vivo, but paradoxically induced killing of betaTC-3 cells even in syngeneic hosts.

Animals↗
PubMed1999

High-resolution holocene environmental changes in the thar desert, northwestern india

Sediments from Lunkaransar dry lake in northwestern India reveal regional water table and lake level fluctuations over decades to centuries during the Holocene that are attributed to changes in the southwestern Indian monsoon rains. The lake levels were very shallow and fluctuated often in the early Holocene and then rose abruptly around 6300 carbon-14 years before the present (14C yr B.P.). The lake completely desiccated around 4800 (14)C yr B.P. The end of this 1500-year wet period coincided with a period of intense dune destabilization. The major Harrapan-Indus civilization began and flourished in this region 1000 years after desiccation of the lake during arid climate and was not synchronous with the lacustral phase.

Journal Article↗
PubMed1999

The role of prophylactic cholecystectomy during splenectomy in children with hereditary spherocytosis.

BACKGROUND/PURPOSE: Hereditary spherocytosis is an autosomal dominant disorder associated with an intrinsic defect in the red blood cell membrane often necessitating splenectomy to prevent sequestration of spherocytes. When cholelithiasis is present, these patients undergo cholecystectomy at the same surgical setting as splenectomy. After splenectomy alone, it is uncertain whether the amount of hemolysis is adequately decreased to prevent subsequent gallstone formation. This study set out to evaluate the frequency in which symptomatic cholelithiasis subsequently develops in children treated by splenectomy alone. METHODS: All patients less than 18 years old with hereditary spherocytosis who underwent splenectomy without cholecystectomy at our institution during the past 27 years were included in this study. A retrospective chart review and telephonic patient follow-up was performed. Gallstones were excluded in these patients either by preoperative ultrasound scan, or by intraoperative palpation of the gallbladder. The main study outcomes of this group included documented cases of cholelithiasis, subsequent need for cholecystectomy secondary to cholelithiasis, and questionnaire to determine the incidence of "subclinical" cholelithiasis (not reported to a physician). RESULTS: Twenty-three subjects were identified who met the inclusion criteria. Complete follow-up data were obtained for 17 of these patients (74%). The mean age at splenectomy was 6.6 +/- 0.69 years, and the mean follow-up was 15.65 +/- 2.03 years (median, 18 years). None of the patients in this series subsequently have undergone cholecystectomy, nor have any had either clinical or subclinical evidence of cholelithiasis since splenectomy. CONCLUSION: Prophylactic cholecystectomy at the time of splenectomy is not indicated in patients with hereditary spherocytosis who do not have gallstones.

Adolescent↗
PubMed1999

Risk factors of delayed extubation, prolonged length of stay in the intensive care unit, and mortality in patients undergoing coronary artery bypass graft with fast-track cardiac anesthesia: a new cardiac risk score.

BACKGROUND: Risk factors of delayed extubation, prolonged intensive care unit (ICU) length of stay (LOS), and mortality have not been studied for patients administered fast-track cardiac anesthesia (FTCA). The authors' goals were to determine risk factors of outcomes and cardiac risk scores (CRS) for CABG patients undergoing FTCA. METHODS: Consecutive CABG patients undergoing FTCA were prospectively studied. Outcome variables were delayed extubation > 10 h, prolonged ICU LOS > 48 h, and mortality. Univariate analyses were performed followed by multiple logistic regression to derive risk factors of the three outcomes. Simplified integer-based CRS were derived from logistic models. Bootstrap validation was performed to assess and compare the predictive abilities of CRS and logistic models for the three outcomes. RESULTS: The authors studied 885 patients. Twenty-five percent had delayed extubation, 17% had prolonged ICU LOS, and 2.6% died. Risk factors of delayed extubation were increased age, female gender, postoperative use of intraaortic balloon pump, inotropes, bleeding, and atrial arrhythmia. Risk factors of prolonged ICU LOS were those of delayed extubation plus preoperative myocardial infarction and postoperative renal insufficiency. Risk factors of mortality were female gender, emergency surgery, and poor left ventricular function. CRSs were modeled for the three outcomes. The area under the receiver operating characteristic curve for the CRS-logistic models was not significantly different: 0.707/0.702 for delayed extubation, 0.851/0.855 for prolonged ICU LOS, and 0.657/0.699 for mortality. CONCLUSION: In CABG patients undergoing FTCA, the authors derived and validated risk factors of delayed extubation, prolonged ICU LOS, and mortality. Furthermore, they developed a simplified CRS system with similar predictive abilities as the logistic models.

Aged↗
PubMed1999

Irinotecan in cancers of the lung and cervix.

Irinotecan is active as a single agent in advanced non-small cell lung cancer (NSCLC), with overall response rates (ORRs) of 13-32% reported in phase II trials. In the first-line treatment of stage III/IV NSCLC, phase II studies have suggested that the combination of irinotecan with cisplatin can achieve response rates of 29-75%, which is greater than achieved with older platinum-containing combinations. Neutropenia and diarrhea are the dose-limiting toxicities. In small cell lung cancer (SCLC), irinotecan alone has achieved ORRs of 16-47% in previously treated SCLC, which is higher than expected with oral etoposide. Studies with irinotecan in combination with cisplatin or etoposide have reported responses of up to 79%. Irinotecan is active in cervical cancer patients whose metastases are outside the area of previous irradiation (ORR 24%) and a major phase II/III study is currently comparing irinotecan as single agent or in combination with cisplatin against a reference cisplatin arm.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Gemcitabine: single-agent and combination therapy in non-small cell lung cancer.

With the advent of several newer agents with single-agent response rates greater than 20% and approximately 30%-40% in combination therapy, non-small cell lung cancer (NSCLC) may now be considered a malignancy that is moderately sensitive to chemotherapy. Examples of these agents include the taxanes, paclitaxel and docetaxel; vinorelbine, a new vinca alkaloid, and the camptothecins, of which CPT-11 is the most actively studied agent. Another new and exciting agent is gemcitabine, a nucleoside analogue structurally related to cytosine arabinoside. Gemcitabine's mechanism of action is activated by deoxycytidine kinase to dFdCMP, dFdCDP and dFdCTP. The latter two compounds, when incorporated into DNA, result in chain termination. Phase I studies using a short infusion schedule given weekly for three weeks followed by one week off established 1,000-1,250 mg/m2/week as the maximum tolerated dose. Single-agent gemcitabine has been extensively studied in patients with chemotherapy-naïve advanced NSCLC with response rates of approximately 20%. Response rates for the combination of gemcitabine plus cisplatin are approximately 28%-54% in phase II trials. Recently, this combination has been studied in randomized phase II and III trials revealing improvements in response rates, time to progression and, in the phase III trial, survival. Current and future studies are evaluating gemcitabine in non-cisplatin combinations (i.e., taxanes).

Antimetabolites, Antineoplastic↗
PubMed1999

First-line combination chemotherapy for advanced non-small cell lung cancer: the Eastern Cooperative Oncology Group and Southwest Oncology Group experience.

Over the past 15 to 20 years we have seen small but significant improvements in the treatment of patients with advanced or metastatic non-small cell lung cancer. By the late 1980s the median survival had increased from approximately 4 months in the untreated patient to approximately 7 to 8 months with traditional cisplatin-based chemotherapy combinations. In the early 1990s several new agents, including the taxanes paclitaxel and docetaxel, gemcitabine, irinotecan, and vinorelbine, demonstrated activity in metastatic non-small cell lung cancer. The combination of cisplatin with some of these newer agents such as vinorelbine or paclitaxel in recent phase II trials resulted in median survivals of approximately 9 to 10 months. Some of these results have been confirmed in large multicenter phase III trials conducted by two US Cooperative groups; the Southwest Oncology Group and the Eastern Cooperative Oncology Group. Their contribution to progress in the treatment of non-small cell lung cancer is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Comparison of epidural anaesthesia with ropivacaine 0.5% and bupivacaine 0.5% for caesarean section.

PURPOSE: To compare ropivacaine 0.5% with bupivacaine 0.5% for epidural anaesthesia for Caesarean section. METHODS: Healthy pregnant women, scheduled for elective Caesarean section were enrolled into this randomized, double-blind, parallel-group study. Epidural block was obtained with 20-30 ml of ropivacaine (group R) or bupivacaine (group B) and surgery started when anaesthesia was reached T6. Maternal heart rate and blood pressure and fetal heart rate were assessed before the test dose and at five minute intervals until the end of surgery. At the same intervals, sensory and motor block characteristics were determined. Apgar scores and Neurologic and Adaptive Capacity Scores (NACS) were determined after delivery. Adverse events were recorded. RESULTS: Sixty-five patients were enrolled and data from 61 were available for analysis; 30 ropivacaine and 31 bupivacaine. Time from the end of the last injection to the start of surgery was 46 +/- 13 min (mean +/- SD) in gp R and 53 +/- 25 min in gp B (P:NS). The median duration of analgesia varied between 1.7 and 4.2 hr in gp R and between 1.8 and 4.4 hr in gp B (P:NS). In patients who developed Bromage 4 block, it persisted longer in those in gp B (2.5 hr) than in gp R (0.9 hr) (P < 0.05). The quality of analgesia was satisfactory in 27/29 patients (93%) in gp R and 27/31 patients (87%) in gp B (P:NS), although supplemental i.v. opioid was required in ten and seven patients, respectively. The most common adverse events in the mother were hypotension (63% gp R and 61% in gp B) (NS) and nausea (30% and 58%, in group R and B, respectively) (P = 0.05). Apgar scores were 7 after five minutes in all neonates. CONCLUSION: Ropivacaine 0.5% and bupivacaine 0.5% provided effective epidural anaesthesia for Caesarean section although supplementation with i.v. opioid was commonly required.

Adolescent↗
PubMed1998

Pharmacokinetics of doxacurium during normothermic and hypothermic cardiopulmonary bypass surgery.

PURPOSE: To compare the pharmacokinetic behaviour of doxacurium in patients undergoing normothermic or hypothermic cardiopulmonary bypass (CPB) for coronary artery bypass graft surgery. METHODS: Twenty patients in two equal groups were studied. Anaesthesia was induced with sufentanil and midazolam after a standard premedication. Doxacurium was administered at 3 x ED95 (80 micrograms.kg-1), and anaesthesia was maintained with 0.5 microgram.kg-1 hr-1 sufentanil, 0.05 mg.kg-1 midazolam and isoflurane 0.5-1%. Systemic temperature for patients in the normothermic and hypothermic groups was maintained at 33-36 C and 26-30 C respectively. Timed blood and urine samples were collected and pharmacokinetic parameters were estimated using a non-compartmental approach. RESULTS: For the normothermic and hypothermic groups, terminal elimination half-life (t1/2 beta) was 100.1 +/- 28 and 183.8 +/- 60 min (P < 0.05) respectively, elimination half-life during the CPB phase (T1/2 CPB) 114.5 +/- 10 and 183.8 +/- 60 min (P < 0.05), mean residence time 108.8 +/- 25 and 164.8 +/- 34 min (P < 0.05) and apparent volume of distribution at steady state 0.20 +/- 0.03 and 0.26 +/- 0.04 L.kg-1 (P < 0.05). Compared with the hypothermic group, the normothermic group had a higher rate of renal clearance (1.40 +/- 0.4 vs 0.93 +/- 0.3 ml.min-1.kg-1; P < 0.05) and a higher value for renal clearance as a percentage of the total clearance (76.2 +/- 10 vs 58.3 +/- 20%). CONCLUSION: The elimination rate of doxacurium during normothermic CPB is faster than that in hypothermic CPB.

Aged↗
PubMed1998

Effects of cigarette smoking and 12-h abstention on working memory during a serial-probe recognition task.

Nicotine has been shown to affect attentional and mnemonic processes. However, whether these effects are due to changes in perceptual and/or motor aspects of the tasks is not at all clear. This study tested the hypothesis that nicotine from cigarette smoking has differential effects on perceptual and motor processes, as reflected by event-related potentials (ERPs) and reaction times (RTs), respectively, and that perceptual effects may be specific to changes in working memory. ERPs. RTs and performance accuracy were recorded from smokers and nonsmokers during a serial-probe recognition memory task in which lists of words or "memory sets" were followed by a probe word that was either in-set or out-of-set. Smokers were tested in a "smoking" and a 12-h "deprived" condition. Smoking-smokers and deprived-smokers exhibited fast RTs to in-set and out-of-set probes relative to a group of nonsmokers. They exhibited even faster RTs when the inset probe word matched the first or last item in the memory set. Thus, smokers as a group showed enhanced primacy and recency effects suggesting that smoking specifically facilitates processes related to the motor output aspects of working memory. Different effects characterized the electrophysiology. Larger P300s were recorded to in-set compared to out-of-set probes by both subject groups. Smoking smokers exhibited enhanced P300s to both types of probes. When smokers abstained for 12 h (deprived smokers), the differences in P300 amplitude were reduced but not eliminated. Smoking smokers exhibited faster P300 latencies to in-set probes, while deprived smokers showed delayed latencies relative to nonsmokers. Primacy and recency P300 effects characterized nonsmokers and deprived smokers. However, this relationship was reversed in the Smoking condition. These results support the hypotheses that nicotine has distinct effects on memory-related perceptual and motor aspects of working memory. The increase in efficiency of the memory search with nicotine is consistent with the functional role of the cholinergic system in maintaining a state "appropriate for efficient information processing."

Adolescent↗
PubMed1998

Paclitaxel plus gallium nitrate and filgrastim in patients with refractory malignancies: a phase I trial.

To determine the maximally tolerated dose of paclitaxel with and without filgrastim (G-CSF) when administered as a 24-hour intravenous infusion after a 120-hour infusion of gallium nitrate at a fixed dose of 300 mg/m2/24 hours, 40 patients were entered onto a trial lasting from September 1994 to September 1996. Eligibility included a diagnosis of an advanced malignancy not amenable to curative therapy and up to one previous chemotherapy regimen for metastatic disease. Gallium was administered at a fixed dose of 300 mg/m2/day as a continuous intravenous infusion for 120 hours. Paclitaxel starting at 90 mg/m2 was given concurrently with the last 24 hours of the gallium as a 24-hour intravenous infusion. Cycles were repeated every 21 days. Once the maximum tolerated dose (MTD) of paclitaxel was reached, G-CSF (5 microg/kg/day days 7-16) was added and paclitaxel dose escalation continued. The MTD for paclitaxel without G-CSF was 110 mg/m2 and 225 mg/m2 with G-CSF, with neutropenia being the dose-limiting toxicity. A partial response was noted in a patient who had thymoma and a complete response was achieved in a patient who had colon cancer. The recommended phase II dosage is gallium nitrate at 300 mg/m2/day over 120 hours, with paclitaxel at 110 mg/m2 over 24 hours without G-CSF or 225 mg/m2 over 24 hours with G-CSF and 0.5 mg calcitriol on days 1 through 7. Further trials of this modified regimen for outpatient administration are in progress.

Adult↗
PubMed1998

Ifosfamide in the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: a phase II Hoosier Oncology Group trial.

The Hoosier Oncology Group conducted a trial evaluating ifosfamide in patients who had recurrent or metastatic squamous cell carcinoma of the head and neck. Patients must have received no prior chemotherapy for metastatic disease. If prior adjuvant chemotherapy was given, the last cycle must have been at least six months from time of recurrence. All patients were required to have a Karnofsky performance status of > or = 50. Twenty-four patients received treatment consisting of ifosfamide, 1.5 g/m2/day for 5 days, with cycles repeated every 3 weeks. Mesna, 300 mg/m2, was administered intravenously 15 minutes before ifosfamide and 4 and 8 hours after ifosfamide on days 1 through 5. Toxicity was predominantly hematologic, with grade 3--4 neutropenia seen in 13 patients resulting in 4 episodes of neutropenic fever. One partial response was seen in 23 evaluable patients for an overall response rate of 4.3% (95% confidence interval, 0, 12.7%). In conclusion, ifosfamide would appear to have limited single-agent activity in squamous cell carcinoma of the head and neck.

Adult↗
PubMed1998

Paclitaxel (Taxol) plus doxorubicin plus filgrastim in advanced sarcoma: a phase II study.

The authors evaluated the novel chemotherapeutic regimen of paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ, U.S.A.) plus doxorubicin plus filgrastim--a granulocyte colony-stimulating factor (G-CSF)--in advanced or metastatic sarcoma. Eligible patients must have had histologically confirmed advanced previously untreated soft-tissue sarcoma. All patients must have had bidimensionally measurable metastases. Treatment consisted of doxorubicin, 50 mg/m2 by intravenous push, followed 4 hours later by paclitaxel, 150 mg/m2 by continuous infusion over 24 hours every 3 weeks, plus G-CSF, 5 microg/kg, on days 3 through 12 of each cycle. Cycles were repeated every 21 days. A one-time dose escalation for doxorubicin only (60 mg/m2) was allowed in all patients who experienced no significant toxicity after their first cycle of paclitaxel plus doxorubicin. From November 1993 through May 1996, 29 patients were entered in this study. Grade 3 anemia occurred in three patients. Grade 3--4 neutropenia occurred in 20 patients. Seven patients experienced at least one episode of neutropenic fever, including one death. Grade 3 thrombocytopenia occurred in four patients. There were six partial responses in 27 eligible patients, for a response rate of 22.2% (95% confidence interval, 7%-38%). Median time to progression was 4.5 months, and median overall survival was 10.2 months. The regimen of paclitaxel plus doxorubicin plus filgrastim as used in this study appears to have no more activity than single-agent doxorubicin.

Adult↗
PubMed1998

CODE (cisplatin, vincristine, doxorubicin, etoposide) plus granulocyte colony-stimulating factor in advanced non-small-cell lung cancer: a Hoosier Oncology Group phase II trial.

This phase II trial investigated the activity and toxicity of CODE (cisplatin, vincristine, doxorubicin, etoposide) chemotherapy with the addition of granulocyte colony-stimulating factor (G-CSF) in patients who had chemotherapy-naive, advanced, or metastatic non-small-cell lung cancer. Treatment consisted of cisplatin, 25 mg/m2, administered weeks 1 through 9; vincristine, 1 mg/m2, weeks 1, 2, 4, 6, and 8; doxorubicin, 40 mg/m2, weeks 1, 3, 5, 7, and 9; and etoposide, 80 mg/m2 intravenously day 1 and 160 mg/m2 orally, days 2 and 3 on weeks 1, 3, 5, 7, and 9. Granulocyte colony-stimulating factor, 5 microg/kg, was administered subcutaneously on all days that patients were not receiving chemotherapy. From April 1992 through April 1993, 42 patients were entered on study. The principal toxicities were hematologic. Grade 3-4 anemia was seen in 21 patients. Grade 3-4 thrombocytopenia was seen in 9 patients. Grade 3-4 neutropenia occurred in 29 patients. Eight patients experienced a neutropenic febrile episode requiring antibiotics. Nonhematologic toxicities included weight loss and fatigue. Responses were seen in 10 of 42 patients, for an overall response rate of 24% (95% confidence interval, 12%-39%) and a median survival of 7.1 months. The CODE chemotherapy regimen has activity similar to other previously described cisplatin-based regimens, with a significant amount of both hematologic and nonhematologic toxicity. Its continued use in patients who have previously untreated non-small-cell lung cancer cannot be recommended, based on the results of this study.

Adult↗
PubMed1998

Is retroperitoneal lymph node dissection necessary for adult paratesticular rhabdomyosarcoma?

PURPOSE: We assess the benefit of retroperitoneal lymph node dissection for adult paratesticular rhabdomyosarcoma. MATERIALS AND METHODS: A total of 19 adults with paratesticular rhabdomyosarcoma who underwent retroperitoneal lymph node dissection between 1980 and 1997 comprise our study population. Postoperative chemotherapy was administered in all patients, including cyclophosphamide, doxorubicin and vincristine with or without consolidation with ifosfamide and etoposide in 17, and vincristine, actinomycin D and cyclophosphamide in 2. Radiation therapy also was administered in 2 patients. Patients were classified into pathological and clinical groups according to the Intergroup Rhabdomyosarcoma Studies. Mean followup was 6.4 years (range 0.5 to 17.6). RESULTS: A total of 17 patients (89%) were disease-free and 2 (1 in pathological group I and 1 in pathological group II) died of disease that recurred outside of the retroperitoneum. Of 16 clinical group I patients 9 were in pathological group II. There were negative nodes in 2 of 3 clinical group II patients. Thus, abdominal computerized tomography correctly staged only 8 of 19 patients (42%). CONCLUSIONS: Retroperitoneal lymph node dissection accurately stages paratesticular rhabdomyosarcoma and eliminates the need for abdominal radiotherapy in patients in pathological group II. Combined modality therapy with retroperitoneal lymph node dissection and postoperative chemotherapy achieves a high cure rate.

Adolescent↗
PubMed1998

The activity of gemcitabine plus cisplatin in randomized trials in untreated patients with advanced non-small cell lung cancer.

Three separate phase III randomized studies were conducted to compare the efficacy of a gemcitabine plus cisplatin combination (GC) with other chemotherapy regimens in the treatment of European and North American patients with inoperable (stage IIIB or IV) non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) compared the GC regimen with an etoposide plus cisplatin combination (EP), the Hoosier Oncology Group (HOG) compared it with single-agent cisplatin, and the Italian Lung Cancer Project (ILCP) compared it with a mitomycin plus ifosfamide plus cisplatin combination (MIC). The three studies each had a different primary objective (response rate, survival, or quality of life, respectively). From July 1995 to February 1997, 751 patients were enrolled into the three studies. In the SLCG study, 69 were entered in the GC arm and 64 in the EP arm; in the HOG study, 155 were entered in the GC arm and 154 in the cisplatin-alone arm; and in the ILCP study, 154 were entered in the GC arm and 152 in the MIC arm. In the SLCG study, gemcitabine 1,250 mg/m2 was given by 30-minute infusion on days 1 and 8 of each 21-day cycle. In the HOG and ILCP studies, gemcitabine 1,000 mg/m2 was given on days 1, 8, and 15 of each 28-day cycle. Cisplatin 100 mg/m2 was given on day 1 in the SLCG and HOG studies and on day 2 in the ILCP study. In the EP arm, etoposide 100 mg/m2 was given on days 1, 2, and 3 of each 21-day cycle. In the MIC arm, mitomycin 6 mg/m2 and ifosfamide 3 g/m2 were given on day 1 of each 28-day cycle. In the SLCG study, 28 patients (40.6%) in the GC arm and 14 patients (21.2%) in the EP arm achieved an objective response (P = .01). In the HOG study, 48 patients (31%) in the GC arm and 14 patients (9.1%) in the cisplatin-alone arm attained on objective response (P < .001). In the ILCP study, 61 patients (40%) in the GC arm and 42 patients (28%) in the MIC arm achieved an objective response (P = .03). Progression-free time was significantly longer for the GC arm (6.8 months) than for the cisplatin-alone arm (4.2 months) (P < .001). The median survival time was remarkably identical for the GC arms in the three studies (8.7 months), whereas it was 7.2 months for the EP arm, 7.6 months for the cisplatin-alone arm, and 9.5 months for the MIC arm. The main toxicities were myelosuppression and vomiting. The assessment of quality of life in the ILCP study is ongoing. Both 21- and 28-day cycles of GC were effective in the treatment of NSCLC, and this combination can be considered as a current "standard" therapy for advanced NSCLC patients.

Adult↗
PubMed1998

Combined cisplatin and gemcitabine for non-small cell lung cancer: influence of scheduling on toxicity and drug delivery.

The scheduling of cytotoxic chemotherapy has important bearing on the toxicity and ability to deliver chemotherapy at or close to full dose. We report new data on the influence of different schedules of cisplatin and gemcitabine on toxicity and drug delivery in phase II studies of non-small cell lung cancer. Patients in six phase II studies had standard entry criteria for advanced non-small cell lung cancer. Whereas gemcitabine was given on days 1, 8, and 15 of a 28-day cycle in all these studies, the scheduling of cisplatin varied and was given either on day 1, day 2, day 15 (in two studies), or days 1, 8, and 15 (in two studies). The protocol dose per infusion for gemcitabine was 1,000 mg/m2 (five studies) and 1,500 mg/m2 (one study); for cisplatin, it was 100 mg/m2 when given once per cycle and 30 mg/m2 when given on days 1, 8, and 15. Similar dose reduction schedules were implemented in the event of grade 3 or higher drug toxicity for all studies except for the day 1 cisplatin study, in which the dose was omitted for grade 2 thrombocytopenia. Nonhematologic toxicity was very low. Hematologic toxicity was moderate, and in patients who developed grade 3 or 4 toxicity, there was no hemorrhage from thrombocytopenia and neutropenic sepsis was rare. The incidence of grade 3 or 4 thrombocytopenia with the day 1, day 2, day 15 (two studies combined), and days 1, 8, and 15 (two studies combined) cisplatin regimens was 50%, 52%, 26%, and 38%. The incidence of grade 3 or 4 neutropenia with these four regimens was 51%, 37%, 56%, and 49%, respectively. Although the hematologic toxicity might appear relatively similar, it represents the toxicity at the administered rather than the intended (protocol) dose, because drug delivery was reduced or omitted in the event of grade 3 or 4 toxicity. Differences between the schedules are revealed by analysis of the actual dosages delivered. The median dosage of gemcitabine per scheduled infusion was statistically higher with the day 15 cisplatin regimens (combined) compared with any of the other regimens treating at 1,000 mg/m2 (P < .003, z-score). The dose with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 664, 829, 889, and 774 mg/m2, respectively. Both the percentages of cycles in which gemcitabine infusions were given at full dose and in which there were no omissions of gemcitabine infusions (including infusions with dose reductions) were statistically higher in the day 15 cisplatin regimen than with any of the other regimens (P < .0001, chi-square test). The percentage of cycles containing full-dose gemcitabine with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 24%, 44%, 75%, and 46%, respectively. The percentage of cycles in which there were no omissions of gemcitabine infusions for the four regimens above was 32%, 55%, 83%, and 72%, respectively. Apart from the once-weekly regimen (days 1, 8, and 15) in which the protocol gemcitabine dose was 1,250 mg/m2, the day 15 cisplatin schedule allowed for the highest median concentration of gemcitabine. More importantly, the day 15 cisplatin schedule provided the longest duration of gemcitabine exposure, which is particularly important for its activity as gemcitabine is a phase-specific agent. The day 15 cisplatin schedule is associated with the best dose intensity and the longest median duration of exposure to gemcitabine, and best meets the goal of administering both agents at full doses in combination.

Adult↗