Biomedical subjects

F A Shepherd

Publications and source records attributed to F A Shepherd.

At least 55 records · Page 3Linked to original sources

PubMed1997

Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin.

PATIENTS AND METHODS: We conducted a randomized, multicenter study of intravenous cyclophosphamide 500 mg/m2 plus fluorouracil 500 mg/m2 combined with either mitoxantrone (Novantrone, Lederle Cyanamid Canada Ltd, Willowdale, Ontario) 10 mg/m2 (CNF) or doxorubicin (Adriamycin, Adria Laboratories of Canada Ltd, Mississauga, Ontario) 50 mg/m2 (CAF) every 3 weeks in advanced breast cancer. RESULTS: The response rate in 249 randomized patients was 36% with CNF (44 of 121) and 48% with CAF (62 of 128) (P = .054), with complete remissions in 10 patients (8.3%) on CNF and in 13 (10.2%) on CAF. If only fully assessable patients are considered, the response rate was 48% (44 of 91) with CNF and 60% (62 of 103) with CAF (P = .098). At time of analysis, all except 10 patients (one CNF and nine CAF) had died. The median survival time with CAF was longer than with CNF (15.2 v 10.9 months; P = .003), and time to progression was also longer with CAF (5.3 v 3.2 months; P < .03). Survival differences remained significant (P = .006) if patients who failed to meet all eligibility criteria were excluded. Favorable prognostic factors for survival in a Cox regression model included good performance status (P < .0001); less than two organ systems involved by tumor (P < .0001); no involvement of lung, liver, or brain (P < .003); involvement of bone or bone marrow (P < .009), prior surgery for breast cancer (P < .006); being premenopausal (P < .03); > or = 3 years from diagnosis until randomization on this study (P < .03); and treatment with CAF (P < .03). Alopecia > or = grade 3 was reported in 55% of patients with CAF and 12% of patients with CNF (P < .001), while other > or = grade 3 toxicities did not differ significantly. Priestman-Baum quality-of-life assessment was comparable on the two study arms. CONCLUSION: In patients with advanced breast cancer, CAF was associated with longer survival than was CNF, with an increase in alopecia, but not in other toxicities.

Adult↗

PubMed1997

Treatment of Kaposi's sarcoma after solid organ transplantation.

PURPOSE: This retrospective review of all patients who developed Kaposi's sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. MATERIALS AND METHODS: The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. RESULTS: Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. CONCLUSION: KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.

Adult↗

PubMed1997

Lung cancer practice guidelines: lessons learned and issues addressed by the Ontario Lung Cancer Disease Site Group.

PURPOSE: The primary objective was to identify the lessons learned and issues addressed by the Disease Site Group (DSG) developing guidelines on lung cancer for practitioners in the province of Ontario. METHODS: The minutes of the Ontario Lung Cancer Disease Site Group (LCDSG) and the meeting notes of a medical sociologist who attended all LCDSG meetings were reviewed to identify the disease-specific and generic issues addressed by the LCDSG during guideline development. RESULTS AND CONCLUSION: The Ontario LCDSG has completed three practice guidelines and has five evidence-based recommendations (EBRs) in production. Topics for guideline development were selected on the basis of known practice variability (eg, advanced-stage non-small-cell lung cancer [NSCLC]); the size of the patient population that could potentially be affected by the guideline; results of phase II trials of new and potentially expensive agents (vinorelbine, paclitaxel, and docetaxel); and randomized controlled clinical trials that support new practice standards (combined modality therapy for unresectable stage III NSCLC). The wording of each EBR reflects the strength and quality of the evidence in support of the treatment option, the primary outcome(s), and the individual physician and discipline values concerning treatment outcomes in the absence of known patient values.

Canada↗

PubMed1997

The role of chemotherapy in the treatment of small cell lung cancer.

Because small cell lung cancer (SCLC) is a systemic malignancy, chemotherapy is the mainstay treatment for patients with all stages of this tumor. Many chemotherapeutic agents have activity against SCLC, and when combined in three- or four-drug regimens, they produce a response in 75% to 90% of patients. Median survival times for patients with limited disease range from 14 to 16 months, and a small proportion may be cured. For extensive stage patients, median survival is usually less than 1 year; 2 year disease-free survival is uncommon. Current research is focusing on ways to increase the dose intensity of chemotherapy delivery.

Antineoplastic Agents↗

PubMed1997

Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer.

Gemcitabine is active against non-small cell lung cancer (NSCLC), with single-agent response rates of 20% or more in previously untreated patients. Its mild toxicity profile suggests that it should be well tolerated by older patients. To assess the impact of age on the efficacy and tolerance of gemcitabine, the results of four phase II trials of single-agent gemcitabine for the treatment of NSCLC were analyzed retrospectively. Starting doses for gemcitabine ranged from 800 to 1,250 mg/m2/wk, and in all studies gemcitabine was administered weekly for 3 weeks followed by a 1-week rest period. Response rates, toxicity, and dose delivery were compared for two age groups, less than 65 years (255 patients) or > or = 65 years (105 patients). The pretreatment characteristics for both patient groups were well balanced. Overall response rates were 16% and 24% for the younger and older patients, respectively (P = .072). Median survival and 1-year survival rates were 8.1 months and 27% and 9.1 months and 36%, respectively, for patients aged less than 65 years and > or = 65 years. Hematologic and nonhematologic toxicities were similar for both age groups. The number of cycles associated with dose reductions or dose omissions and the mean number of treatment cycles administered were also similar. In summary, gemcitabine is active and well tolerated in elderly patients with NSCLC, and is a promising new alternative for the treatment of this patient population.

Aged↗

PubMed1997

Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer.

Single-agent gemcitabine, when given in doses of > or = 1,250 mg/m2 weekly x 3 with a 1-week break, induces responses in approximately 20% of untreated patients with non-small cell lung cancer. This phase II study was undertaken to determine the efficacy of weekly administration of gemcitabine 1,500 mg/m2 combined with cisplatin 30 mg/m2 x 3 with a rest period of 1 week. Patients younger than 75 years were eligible if they had stage III/IV non-small cell lung cancer, a life expectancy > or = 12 weeks, hemoglobin > or = 10 g/dL, absolute granulocyte count > or = 10(9)/L, platelets > or = 100 x 10(9)/L, hepatic enzymes no more than three times the upper limit of normal, and serum creatinine < or = 130 micromol/L. There were 22 men and 18 women, with a median age of 60 years; 35 had a performance status of 0 or 1. Pathology included adenocarcinoma in 22 patients, squamous cell carcinoma in nine, large cell carcinoma in seven, and mixed non-small cell lung cancer in two. Six patients had stage III and 34 had stage IV tumors. Of the 39 patients eligible for response evaluation, partial remission was seen in 10, for an overall response rate of 26% (95% confidence interval, 12% to 41%). The median duration of response was 19 weeks (range, 7 to 32+ weeks). Grade 3/4 anemia was seen in 11 patients, and 21 patients required red blood cell transfusions. Grade 3/4 neutropenia occurred in 22 patients and grade 3/4 thrombocytopenia in 21 patients. One patient experienced febrile neutropenia Hematologic toxicity, particularly thrombocytopenia, was cumulative over time. Nonhematologic toxicity was modest, but one patient stopped therapy because of a grade 2 skin rash and one stopped because of a grade 4 pulmonary toxicity, both of which were thought to be related to gemcitabine. The modest activity of weekly gemcitabine and weekly cisplatin seen in this trial does not suggest in vivo synergy for these two agents as administered using this schedule and these doses.

Adult↗

PubMed1996

Phase I trial of gemcitabine and cisplatin in advanced non-small cell lung cancer: a preliminary report.

A phase I trial was performed to investigate the tolerability and efficacy of the novel nucleoside analogue gemcitabine in combination with cisplatin in the treatment of advanced non-small cell lung cancer. Both cisplatin and gemcitabine were administered as 30 min infusions weekly x 3 with a week of rest. There was one dose escalation of cisplatin from 25 mg/m2 (dose level 1) to 30 mg/m2 (in subsequent dose levels 2-5), such that the mean dose intensity for the weekly x 3 q 4 week cycle was 22.5 mg/m2/week which is close to that achieved with 100 mg/m2 bolus monthly. Gemcitabine was initiated at 1000 mg/m2 (dose levels 1 and 2) then escalated by 250 mg/m2/week to 1750 mg/m2 (dose level 5). Of 32 chemotherapy-naive patients entered (22 males, 10 females; median age 61 years, range 29-74 years), 11 had localized tumours (2 stage IIIa, 9 IIIb) and 21 had stage IV tumours with haematogenous metastases and a poor prognosis. Twenty-one patients had adenocarcinoma, 4 squamous cell carcinoma, 6 large cell undifferentiated tumors, and one had mixed squamous and adenocarcinoma. Dose-limiting toxicity was not seen in more than one patient in cycle 1 at any dose level. Grade 4 granulocytopenia and thrombocytopenia occurred more frequently with repeated dosing, necessitating dose reductions except at the lowest dose level (cisplatin 25 mg/m2, gemcitabine 1000 mg/m2). Non-haematological toxicity was mild and rapidly reversible. Cisplatin administration led to a higher frequency of nausea and vomiting than that seen with gemcitabine alone, but this was easily controlled with antiemetics. In the 28 patients evaluable, to date responses have been seen at most dose levels, with an overall response rate 35.7%. This phase I trial is ongoing and further dose escalation is intended to determine the MTD of gemcitabine.

Adult↗

PubMed1996

Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study.

Gemcitabine is a novel nucleoside analogue with activity in solid tumours. This study assessed the objective response rate to gemcitabine given weekly intravenously at a dose of 1250 mg/m2 for 3 weeks followed by 1 week of rest (one cycle) in chemonaive patients with inoperable non-small cell lung cancer (NSCLC). 161 patients with NSCLC were recruited from 10 sites in nine countries. Most patients had stage IIIb (31.3%) or IV (64.6%) disease, and 93.8% had a performance status of 0 or 1 according to the WHO scale. Of 151 evaluable patients, there were 3 complete responses and 30 partial responses lasting at least 4 weeks for an objective response rate of 21.8% (95% CI 15.5-29.3%). All responses were validated by an extramural Oncology Review Board. The mean duration of response was 8.8 months. The mean survival for all patients (16.1% of patients still alive 26 months after last patient started treatment) was 11.5 months. Improvements were also observed in secondary efficacy parameters such as performance status, weight, analgesic requirement, pain, and other disease-related symptoms including cough, dyspnoea, haemoptysis, anorexia, somnolence and hoarseness. Haematological and non-haematological toxicity was mild given the biological activity of gemcitabine. This study confirms gemcitabine as one of the most active agents in NSCLC with the added benefit of a modest toxicity profile and ease of administration on an out-patient basis. Gemcitabine is a suitable candidate for combination chemotherapy in patients with NSCLC.

Adolescent↗

PubMed1996

Pericardial sclerosis as the primary management of malignant pericardial effusion and cardiac tamponade.

OBJECTIVES: The management of malignant pericardial effusion remains controversial. We present our experience with 93 patients referred for drainage and sclerosing procedures between 1979 and 1994. METHODS: With continuous electrocardiographic monitoring, a Kifa catheter was inserted percutaneously into the pericardial sac and allowed to drain. A 100 mg dose of lidocaine hydrochloride was instilled intrapericardially, followed by 500 to 1000 mg tetracycline or doxycycline hydrochloride in 20 to 50 ml normal saline solution. The catheter was clamped for 1 to 2 hours and then reopened, and the procedure was repeated daily until the net drainage was less than 25 ml in 24 hours. RESULTS: Subjects included 53 women and 40 men (median age 58 years). Eight patients could not undergo sclerosis because of technical failure. Eighty-five patients underwent sclerosis and required a median dose of 1500 mg of the sclerosing agent (range 500 to 700 mg), given in a median of three injections (range one to eight). Complications included pain (17 patients), atrial arrhythmias (eight patients), fever with temperature greater than 38.5 degrees C (seven patients), and infection (one patient). Two patients had cardiac arrest before sclerosis could be attempted. Sixty-eight patients (73%) had the effusion controlled for longer than 30 days, for an overall control rate of 81%. Seven other patients had control of the effusion but died of progressive malignant disease in less than 30 days. The overall median survival was 98 days (range 1 to 1724 days). Comparison of these results with outcomes reported for patients with malignant pericardial effusion who underwent surgical drainage indicates that drainage and sclerosis provide similar survivals but sclerosis carries lower morbidity, mortality, and recurrence rates. CONCLUSION: Percutaneous drainage and sclerosis constitutes a safe and effective treatment for malignant pericardial effusion. Surgical management should be reserved for the small percentage of cases that cannot be controlled by this method.

Adult↗

PubMed1996

Phase I study of paclitaxel (Taxol) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer. A study of the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Paclitaxel (Taxol) and ifosfamide are among the most active single agents for the treatment of non-small-cell lung cancer. We undertook this phase I dose escalation study to determine the maximum tolerated doses of these drugs which could be administered without growth factors to untreated patients with tumours of this type. PATIENTS AND METHODS: Forty patients with advanced non-small-cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide every 3 weeks. Groups of 3 patients were entered at escalating dose levels in traditional phase I design. Starting doses were paclitaxel, 100 mg/m2, and ifosfamide 3 g/m2, and all patients received premedication with dexamethasone, diphenhydramine and a 5-HT3 blocker. Dose escalation occurred only after full toxicity assessment for 2 cycles for all patients in the dose level. RESULTS: Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neuro-toxicity above this level. Instead, ifosfamide was increased to 4 g/m2 for the final level. At these doses, dose-limiting myelosuppression was not seen, and there was only 1 episode of febrile neutropenia in 164 treatment cycles. Drug-related toxicities of ifosfamide included gross hematuria and confusion in 1 patient each, and paclitaxel-related symptoms included flu-like syndrome in most patients, mild to moderate arthralgia and/or myalgia in 8 and 25 patients, respectively, parasthesiae in 15 patients and mild to moderate hypersensitivity reactions in 15 patients each. Partial response was seen in 20.5% of patients (CI 9.3%-36.5%). SUMMARY: Out-patient paclitaxel given over 3 hours and single-dose ifosfamide over 1 hour may be combined safely without the need for hematopoietic growth factors for the treatment of patients with non-small-cell lung cancer. The recommended doses for phase II study are paclitaxel, 225 mg/m2 and ifosfamide, 4 g/m2 every 3 weeks.

Adult↗

PubMed1996

Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade.

PURPOSE: To compare the clinical efficacy and toxicity of doxycycline and bleomycin as sclerosing agents in the primary management of malignant pericardial effusion (MPE). METHODS: Twenty-seven consecutive adult patients referred to a tertiary-care institution for the management of cardiac tamponade and malignancy underwent pericardial drainage through a percutaneously placed pigtail catheter. They were then alternately assigned to undergo bleomycin or doxycycline pericardial sclerosis. RESULTS: There were 13 men and 14 women, with a median age of 59 years. They mainly had lung (70%) and breast cancers (11%), and all had clinical and echocardiographic evidence of cardiac tamponade. Although all patients had successfully placed catheters, six were inadvertently dislodged before sclerosis; 11 underwent bleomycin sclerosis and 10 doxycycline sclerosis. Twenty patients (one early death) were assessable. One patient in each group failed to respond to sclerosis with the initial agent, but both were sclerosed successfully with the other agent. Sclerosis was achieved with a median of two instillations for each agent and total median doses of bleomycin 20 mg and doxycycline 1,250 mg. Seventy percent of doxycycline patients developed significant retrosternal pain, compared with no bleomycin patients (P = .04). Doxycycline patients required a median of 3.5 more days of hospitalization (8.5 v 5) and 2 more days of pericardial catheterization (7 v 5) compared with bleomycin patients. Tamponade recurred in one bleomycin patient at 253 days, and in no doxycycline patient. CONCLUSION: Although bleomycin and doxycycline are equally effective sclerosing agents, bleomycin is associated with significantly less morbidity and should be the first-line chemical sclerosing agent for malignant pericardial effusions.

Adult↗

PubMed1996

Influence of age on the treatment of limited-stage small-cell lung cancer.

PURPOSE: To evaluate the prognostic importance of age on response rate and survival in patients with limited-stage small-cell lung cancer (SCLC), and to determine the effect of age on chemotherapy dose delivery and toxicity. PATIENTS AND METHODS: We undertook a retrospective analysis of data from two multicenter, randomized trials conducted by the National Cancer Institute of Canada (NCIC) in which 608 SCLC patients who presented with limited disease (LD) all received the same chemotherapy. Treatment consisted of cyclophosphamide, doxorubicin, and vincristine (CAV), and etoposide plus cisplatin (EP) administered in an immediate or delayed alternating fashion, plus cranial and thoracic irradiation. RESULTS: There were 520 patients aged less than 70 years, and 88 > or = 70. No significant differences existed between the two age groups in baseline characteristics, including treatment protocol, performance status, and serum lactate dehydrogenase (LDH) level. There were more men in the older group (P = .05). Overall response rates were comparable (78% v 82%, P = .50), and 5-year survival rates were also similar (P = .14), with 11% alive in the younger group and 8% in the older group. Age was a significant predictor of overall survival when analyzed as a continuous variable in a univariate model (P = .01), but it was no longer an independent prognostic factor in our multivariate regression analysis. An analysis of chemotherapy delivery between the two age groups showed that patients aged > or = 70 years received lower total doses of each drug compared with the intended full protocol dose, primarily as a result of dose omissions, rather than dose reductions. The frequency of dose delays was not different between groups. No significant differences were seen in the incidence of either hematologic or most nonhematologic toxicities. CONCLUSION: Age is not a significant adverse prognostic variable in SCLC patients with LD. Moderately aggressive chemotherapy may be delivered safely to elderly patients with a good performance status, although modest attenuation of therapy through either dose reduction or omission may occur more frequently in this population.

Adolescent↗

PubMed1996

Phase I dose-escalation trial of gemcitabine and cisplatin for advanced non-small-cell lung cancer: usefulness of mathematic modeling to determine maximum-tolerable dose.

PURPOSE: This study was undertaken to determine the maximum-tolerated doses of gemcitabine and cisplatin, each given weekly for 3 weeks with a 1-week rest. PATIENTS AND METHODS: Patients less than 75 years of age were eligible if they had stage III/IV non-small-cell lung cancer (NSCLC), life expectancy > or = 12 weeks, hemoglobin level > or = 10 g/dL, granulocyte count > or = 2 x 10(9)/L, platelet count > or = 100 x 10(9)/L, hepatic enzymes < or = three times the upper limit of normal, and creatinine concentration < or = 130 mumoles/L. The starting doses for gemcitabine and cisplatin were 1,000 mg/m2 and 25 mg/m2 per week for 3 weeks. At dose level 2, cisplatin was increased to 30 mg/m2/wk for 3 weeks, and thereafter only gemcitabine was increased by 250 mg/m2/wk at each dose level to a maximum of 2,250 mg/m2/wk. RESULTS: There were 33 men and 17 women, with a median age of 62 years. Pathology included adenocarcinoma in 35 patients, squamous in eight, large cell in six, and mixed histology in one. Sixteen patients had stage III and 34 had stage IV tumors. The median nadir granulocyte and platelet counts decreased with each dose level, but cycle 1 dose-limiting toxicity (DLT) in > or = two patients was not encountered in cycle 1, even at the highest dose level. Cumulative marrow toxicity was seen at all levels, which resulted in frequent dose reductions or omissions. A mathematic model of all toxicities over time suggested that dose level 4 (cisplatin 30 mg/m2/wk and gemcitabine 1,500 mg/m2/wk) would be the maximum dose at which grade 4 toxicity would be expected in < or = 33% of patients over four cycles. Of 47 assessable patients, 14 achieved a partial response (30%; confidence interval, 17% to 43%). The median duration was 16 weeks and the median survival time was 24 weeks (range, 3.5-64+). CONCLUSION: Weekly gemcitabine and cisplatin are active against NSCLC, and the recommended phase II doses are 30 and 1,500 mg/m2/wk for 3 weeks, respectively.

Adenocarcinoma↗

PubMed1996

Final results of the Canadian phase I dose escalation trial of gemcitabine and cisplatin for advanced non-small cell lung cancer.

When given at doses of > or = 1,250 mg2 weekly x 3 with a 1-week break, single-agent gemcitabine induces responses in more than 20% of previously untreated patients with non-small cell lung cancer (NSCLC). This study was undertaken to determine the maximum tolerated doses for a 4-week cycle of gemcitabine and cisplatin given in combination weekly x 3 with a 1-week rest. Patients younger than 75 years were eligible if they had stage III/IV NSCLC, life expectancy > or = 12 weeks, hemoglobin > or = 10 g/dL, absolute granulocyte count > or = 2 x 10(9)/L, platelets > or = 100 x 10(9)/L, hepatic enzymes < or = 3 times the upper limit of normal, and serum creatinine < or = 130 mumol/L. The starting doses for gemcitabine and cisplatin were 1,000 mg/m2 and 25 mg/m2 per week x 3, respectively. At dose level 2 cisplatin was increased to 30 mg/m2/week x 3. Thereafter only the gemcitabine was increased, by 250 mg/m2/wk at each dose level, to a maximum of 2,250 mg/m2/wk at dose level 7. The median nadir granulocyte and platelet counts decreased with each dose level, but dose-limiting toxicity in two or more patients was not encountered in the first treatment cycle, even at dose level 7. Cumulative bone marrow toxicity was seen at all dose levels, and this resulted in frequent dose reductions or omissions. Dose delivery was well maintained over time only at dose level 1. Grade 3-4 nonhematologic toxicity was infrequent and rarely dose limiting. An assessment of all toxicities seen during the treatment cycles was undertaken using continual reassessment methodology. This model suggested that dose level 4 (cisplatin 30 mg/m2/wk and gemcitabine 1,500 mg/m2/wk) would be the maximum dose at which grade 4 toxicity would be expected in up to 33% of patients at any time over four treatment cycles. Of 47 patients evaluable for response, partial remission was seen in 14, with an overall response rate of 30% (confidence interval, 17% to 43%). The median duration of response was 16 weeks and the median survival time was 24 weeks (range, 3.5 to 64+ weeks). A phase II trial is planned in which dose level 4 will be evaluated in a larger cohort of patients with NSCLC.

Adult↗

PubMed1996

Phase I dose-escalation trial of paclitaxel and ifosfamide in patients with advanced non-small cell lung cancer.

This phase I dose-escalation study was undertaken to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide that could be administered without growth factors to previously untreated patients with non-small cell lung cancer. Forty patients with advanced non-small cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide, repeated every 3 weeks. Groups of three patients each entered at escalating dose levels in a traditional phase I design. Starting doses were paclitaxel 100 mg/m2 and ifosfamide 3 g/m2; all patients received premedication with dexamethasone and diphenhydramine, and some also received a 5-HT3 blocker. Dose escalation was permitted only after full toxicity assessment had been completed for two cycles for all patients at a dose level. Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this dosage. Instead, ifosfamide was increased to 4 g/m2 for the final dose level. At these doses, dose-limiting myelosuppression was not seen, and there was only one episode of febrile neutropenia in 162 treatment cycles. Drug-related ifosfamide toxicities included gross hematuria and confusion in one patient each; paclitaxel-related symptoms included flu-like syndrome in most patients, arthralgia and/or myalgia in eight and 25 patients, respectively, and paresthesia in 14 patients. Despite premedication, 15 patients experienced grade 1 hypersensitivity reactions. Partial response was seen in 21% of patients (confidence interval, 9.3% to 36.5%), and the median duration of response was 5.9+ months (range, 3 to 14 months). The median survival was 9.1 months (range, 1 to 12 months). In summary, outpatient paclitaxel given over 3 hours and single-dose ifosfamide given over 1 hour may be combined safely without hematopoietic growth factors for the treatment of patients with non-small cell lung cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and ifosfamide 4 g/m2, every 3 weeks.

Adult↗

PubMed1995

Gemcitabine in the treatment of non-small-cell lung cancer.

Gemcitabine is a nucleoside analogue with activity in non-small-cell lung cancer (NSCLC). Phase I trials have determined the best tolerated dose of gemcitabine in chemotherapy-naive patients to be 1250 mg/m2 given as a 30-minute infusion weekly x 3 every 4 weeks. The single-agent efficacy of gemcitabine has been assessed in 4 phase II trials (361 patients) at dose of 800-1250 mg/m2/weekly x 3 every 4 weeks. Single-agent response rates (externally verified by Oncology Review Board) were > 20%, with duration of response 7.6-12.7 months and median survival 8-9 months. Dose-limiting toxicity was neutropenia, but this was rare, even at the highest dose levels. In 3 Japanese studies, response rates of 16.3%, 26% and 20.9% were seen in untreated patients. Pooled data from all NSCLC studies shows that responses were seen in stages IIIA, IIIB and IV disease, and were similar in adeno and squamous cell types. Gemcitabine has also been studied in combination with other drugs active in NSCLC. In one study 50 patients were treated with gemcitabine and cisplatin given weekly x 3 every 4 weeks, cisplatin at a dosage of 25-30 mg/m2 and gemcitabine at doses escalating from 1000 mg/m2 in steps of 250 mg/m2 per cycle, 38 of 50 patients have been evaluated to date, with an overall response rate of 31.6%. Dose limiting toxicity was rare, but there was evidence of cumulative haematological toxicity with grade 4 granulocytopenia and thrombocytopenia becoming more frequent with repeated administration. Similar activity was seen when gemcitabine (1000 mg/m2) was combined with monthly cisplatin (60, 75, 100 mg/m2). Other studies have shown that gemcitabine can enhance radiosensitivity in NSCLC and other solid tumour types such as pancreas/breast and colorectal cancer cell lines.

Antimetabolites, Antineoplastic↗

PubMed1995

Intrathoracic complications of malignancy and its treatment.

Obstruction of the superior vena cava is seldom a true emergency and should not be treated without an adequate tissue diagnosis. For patients who are poor operative risks for invasive procedures, percutaneous biopsies of mediastinal masses under ultrasound guidance have resulted in a high diagnostic yield. Superior vena caval syndrome secondary to thrombosis is increasing as venous access devices are used more commonly, and it is important that the catheter should be positioned well down in the vena cava to prevent thrombotic complications. Talc remains the best agent to achieve sclerosis of the pleural cavity, but doxycycline and minocycline are also quite effective replacements for tetracycline, which is no longer available. Radiation-induced pneumonitis and esophagitis continue to limit the total dose and the field that may be administered within the thoracic cavity. As combined modality treatment programs are developed and as doses of chemotherapeutic agents and radiation are both intensified, steps must be taken to ensure that the added toxicity of such treatment can be justified by a significantly superior outcome.

Airway Obstruction↗

PubMed1995

Phase II trials of single-agent activity of gemcitabine in patients with advanced non-small cell lung cancer: an overview.

A total of 361 patients have been entered into four phase II trials in which gemcitabine was given as a 30 min infusion in a schedule weekly x 3 q4W, at starting doses of 800-1250 mg/m2. Three of these trials produced response rates of 22.5%, 20% and 21.8% (all response rates were independently evaluated by an extramural Oncology Review Board). One small study of 30 evaluable patients produced a disappointing low response rate of 3%, but in this study the mean and median dose delivered was under 700 mg/m2. Gemcitabine was well tolerated with modest levels of traditional cytotoxicities such as myelosuppression, nausea and vomiting, and alopecia. Pooled data from two of the studies show improvement in a number of disease-related symptoms. Objective response rates by prognostic factor were determined: stage IIIa (30.5%), stage IIIb (18.8%), stage IV (19.5%); performance status 0 (31.8%), 1 (16.7%) and 2 (21.7%); female gender (23.5%), male (17.5%); age < 70 (18.6%), age > 70 (21.9%). Gemcitabine can be considered for use as a single agent in patients unable or unwilling to tolerate combination chemotherapy. Dose-response data suggest that a dose of 1000 mg/m2 or more is required for optimal therapeutic effect. The single-agent activity of gemcitabine together with its non-overlapping toxicity and novel mode of action suggest that this agent should also be investigated in combination with other active agents in non-small cell lung cancer.

Adult↗